The major aims of this project have been accomplished through establishment of a large community based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, we have enrolled 344 participants into the study from the community, and 238 from clinical sources. Our total enrollment from all sources is 786 probands, of which almost 500 have completed the study, and 1,283 relatives, including 175 children. Over the past year, 11 probands and 49 relatives have been recruited. Probands represent a range of disorders including: 30% with bipolar, 63% with depression, 60% with anxiety, 50% with migraine, and 22% without any of these conditions. During the next 3 months we plan to complete recruitment of probands and evaluation of relatives and will commence data analysis. In order to identify the core features of mood and anxiety disorders and their overlap with cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. The comprehensive set of measures in the study are divided into three components: (1) clinical information that includes a semi-structured diagnostic interview for mood and anxiety disorders, structured diagnostic interviews for major headache syndromes and for sleep disorders, family history of psychiatric disorders, sleep disorders and headache syndromes, and a series of self-reported measures of symptoms, sleep patterns and personality, medical history, family structure, history and function, and major life and family events; (2) in person evaluation at the NIH Clinical Center that includes physical and neurological examination; autonomic nervous system evaluation using tilt and valsalva maneuver; laboratory measures of metabolic, cardiovascular, and immunologic function; psychophysiologic evaluation including startle reflex and eyeblink reflex; structural magnetic resonance imaging; a computerized cognitive assessment battery; and olfactory function; and (3) two-week assessment of daily activities including an electronic diary that assesses daily rhythms including mood, anxiety, sleep, stress, activity, diet, and social activities; heart rate reactivity using a holter monitor; activity and sleep using an actiwatch; and saliva hormones collected four times per day. In the past year, we have been running preliminary analyses on several of these clinical components and working with external collaborators to design and implement analyses of all of the measures in the study. This study has yielded substantial methodological developments including the development and validation of a structured diagnostic interview for headache syndromes; systematic assessment of the validity of the NIMH Family Study Diagnostic Interview for Affective Spectrum Disorders that was developed for this study compared to the Structure Clinical Interview for DSM-IV (SCID); and the validity of the NIMH Sleep Diagnostic Interview also developed for this study compared with sleep disorder diagnoses made by sleep experts. We have completed the primary analyses of the familial aggregation of mood disorder subtypes, their patterns of comorbidity, and their co-aggregation in relatives, and have submitted the principal paper that reports these findings. Likewise, we have also completed analyses of the familial aggregation of migraine and comorbid conditions. The major findings confirm the familial aggregation of bipolar disorder and major depression that has been found in earlier family studies of mood disorders but in a community based sample that suspended diagnostic hierarchies of earlier diagnostic systems. The most important finding that emerged from this study is the independent familial transmission of mania and depression suggesting that these two mood states may represent distinct underlying diatheses. The lack of familial aggregation of hypomania suggests that the bipolar spectrum concept may not be a valid entity. We also found strong evidence for familial specificity of atypical depression in probands and interviewed relatives, thereby confirming the validity of this subtype of depression. We also have investigated the familial aggregation of migraine and its links with mood disorders. We found a 2.6-fold increased risk of migraine in the relatives of probands with migraine, primarily attributable to migraine with aura. Sex of the proband was not associated with differential risk of migraine in relatives, thereby indicating that the sex difference in migraine cannot be attributed to genetic factors. Additional analyses that are now being investigated include the familial aggregation of subtypes of sleep disorders, early manifestations of mood and anxiety disorders in offspring of parents with mood spectrum disorders, and heritability analyses of both disorders and underlying traits. During the past several months, we have begun to examine the non-clinical measures as well, with substantial progress in analysis of the eyeblink reflex, actigraphy, olfactory measures and attention using the Attention Network Test. We have also conducted extensive analyses of links between cardiovascular disease and risk factors, migraine and depression in other data sets to develop specific hypotheses for the analyses of the family study data. Some intriguing findings that have emerged include: greater reactivity of the eyeblink reflex among those with migraine with aura compared to those without aura and non-headache controls; greater variability in activity among those with major depression; and increased orienting to cues in those with migraine with aura, and decreased speed of attention among those with depression. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: During the next year, we plan to follow up the probands and relatives to update the diagnostic status, and repeat the measures of circadian rhythms of activity, sleep and cognitive and mood states to test their stability and seasonal changes. We will complete enrollment of children under age 18 and follow up the 150 youth who have already participated in the study. Finally, we will examine common measures to match the NIMH local community to the supplemental study that we are now conducting in the Neurodevelopmental Genomics Study at the University of Pennsylvania.